Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). Persistent infections caused by HCV occur in 70-80% of acutely infected individuals, the majority of which will develop chronic hepatitis and will be at risk for cirrhosis, end-stage liver disease and/or hepatocellular carcinoma. Liver damage from chronic hepatitis C virus infection is now the most common cause of liver transplantation in the US.
HCV infection is treated with antiviral medications, e.g. pegylated interferon administered alone or in combination with ribavirin. Combination therapy with pegylated interferon and ribavirin is now successful in about half of the cases, but it is currently prohibitively expensive, requires long-term treatment, and is associated with serious side effects. In much of the world, such treatments are not economically feasible. New direct-acting antiviral drugs such as protease and polymerase inhibitors, either with or without interferon and/or ribavirin, have the potential to increase the response rate and to decrease the duration of treatment. However, these drugs may also have significant side effects and are extremely expensive. Two protease inhibitors are now approved in the United States for use in combination with interferon and ribavirin although the treatment costs are between $26,000-$49,000 per patient depending on the treatment duration, in addition to the costs for pegylated interferon and ribavirin (Tungol, A. et al., J Manag Care Pharm (2011) 17:685-94).
At present, there are about 17,000 new HCV infections each year in the U.S., making the development of a vaccine against this virus imperative.
The natural variability of HCV, resulting in the coexistence of quasispecies in infected individuals, could be important in hepatitis C pathogenesis. It has been postulated that immune pressure on these variants brings about the selection of escape mutants able to overcome host immune responses and establish persistent infection. The greatest genetic variability is observed in the E1 and E2 glycoproteins, posing problems for vaccine development and providing potential for escape from vaccine-induced immune responses.
The role of neutralizing antibody (nAb) in controlling viral replication during primary or secondary HCV infections is still unclear. High titers are not produced until the chronic phase of the infection. Although induction of nAbs has been associated with clearance of HCV, such antibodies may not be an absolute requirement. However, antibodies to HCV surface proteins can neutralize virus in vitro and chimpanzee vaccine studies using recombinant envelope glycoproteins (rE1E2) have shown modified infections and increased rates of clearance. Monoclonal antibodies (mAbs) have been identified that are capable of cross-neutralizing a number of different genotypes (GTs) in vitro, however, the challenge of how to induce such antibodies efficiently by vaccination, for example with recombinant antigens, still remains. Often peptide vaccination does not induce antibodies with the desired immunogenic effects and there exists very little information on antibody profiles induced by immunization with recombinant antigens or the titers of antibodies to specific neutralization epitopes.
Further, a major challenge facing HCV infected patients that undergo liver transplants is recurrence of hepatitis C virus infection following otherwise technically successful liver transplantation. Recurrent HCV infection leads to diminished graft and patient survival. Although a number of predictors of severe recurrence have been identified, no definitive strategy has been developed to prevent recurrence. Although hepatitis B virus (HBV)-specific antibody products exist that are effective in preventing recurrence of HBV infection in liver transplant patients, no HCV-specific vaccine or prophylactic treatment is available yet for preventing recurrence of HCV infection in liver transplant patients.
There remains a need in the art for more treatments of and vaccines to prevent HCV infection.